1. Field of the Invention
The present invention relates to a novel octahydro-2-naphthalenecarboxylic acid derivative (hereinafter designated as compound TAN-1813) useful as a farnesyltransferase inhibitor, and its production and use.
2. Description of Related Art
Ras gene is widely conserved in eukaryotic cells. Recent studies have revealed that ras gene product (ras protein) plays important roles as a signal transducer in regulating cell growth and differentiation. Further, point mutation of ras gene is frequently observed in various tumors. It is well established that mutated ras Proteins are always fixed in a GTP-bound activated form, and thereby the growth-promoting signal is always transduced (Cancer Research 49, 4682 (1989)). The ras protein is a GTP-binding protein having a molecular weight of about 21,000. Farnesylisoprenoid is attached to the C-terminal cysteine residue of the protein by three steps of post-translational modifications. It is believed that the growth-promoting signal is transferred only when the protein is localized in cell plasma membrane using the farnesylisoprenoid as an anchor (Nature 310, 583 (1984), Proceedings of the National Academy of Science, USA 86, 6630 (1989), etc.). Therefore, it is expected that inhibition of ras protein farnesylation blocks function of the ras protein, and thereby inhibits growth of the tumor harboring ras mutation.
On the other hand, a unique amino acid sequence motif is observed in the C-terminal region of ras protein. The amino acid sequence motif is represented by CAAX wherein C is cysteine, A is an aliphatic amino acid and X is usually serine or methionine (Annual Review of Biochemistry) 61, 355 (1992), Annual Review of Genetics 30, 209 (1992), etc.). Farnesyltransferase was isolated from rat brains as an enzyme that recognizes the CAAX motif of ras protein to transfer farnesylpyrophosphate, a cholesterol biosynthetic intermediate, to the cysteine residue (Cell 62, 81 (1990)).
Examples of microbial substances having farnesyltransferase-inhibitory activity are 10'-desmethoxystreptonigrin, gliotoxins, pepticinnamins, manumycins, zaragozic acids, chaetomellic acids (Trends in Biochemical Sciences 18, 349 (1993)), patulin (FEBS Letters 318, 88 (1993)), etc. Synthetic peptides that are analogues of the tetrapeptide CAAX (Science 260, 1934-1942 (1993), etc.), and synthetic analogues of another substrate, farnesylpyrophosphate (Lipid 28, 969 (1993), etc.) have also been reported as farnesyltransferase-inhibitory substances.
The farnesyltransferase-inhibitory substances described above have some disadvantages. For example, some of them have been proved to be metabolically unstable, to be impermeable to cells and/or have another biological activity other than farnesyltransferase inhibition and thus have poor specificity, leading to adverse side effects. Therefore, there is a need for novel farnesyltransferase inhibitors that are stable in vivo and have high specificity.
One object of the present invention is to provide a novel compound having farnesyltransferase-inhibitory, cell growth-inhibitory, and anti-tumor activities.
Another object of the present invention is to provide a farnesyltransferase-inhibiting agent.
Another object of the present invention is to provide an anti-tumor agent.
Another object of the present invention is to provide a microorganism capable of producing the novel compound.
These objects as well as other objects and advantages of the present invention will become apparent to those skilled in the art from the following description with reference to the accompanying drawings.